1. Field of the Invention
The present invention is concerned with implantable devices having a polymer layer containing one or more therapeutic agents, i.e., a medicament or medicaments, which devices are implantable into specific sites, such as tumors or lesions, in a patient's body for sustained time-release of the one or more medicaments into the specific site, and to methods of making and using such implantable devices.
2. Related Art
Modern solid tumor cancer therapy typically proceeds along multiple fronts. Surgical resection, radiotherapy, and chemotherapy are the most common treatment modes, and they are ordinarily used in various combinations. For instance, resection procedures are usually followed by radiotherapy and/or chemotherapy in an attempt to eliminate metastatic cells which have traveled from the tumors. These treatments are usually traumatic for patients, and often fail to eliminate the disease.
Surgical resection involves the removal of neoplastic tissue along with contiguous tissue, which may contain some tissue that was inadvertently released from the tumor during the resection procedure. For this reason, resection is usually followed by radiotherapy and/or chemotherapy. The procedure is traumatic, and leads to physical and esthetic deformation. The procedure exposes patients to high risks of hospital-acquired nosocomial infections which may be difficult to treat because drug resistant organisms (Super Bugs) are often involved, and the patients are often immunocompromised because of disease.
Radiotherapy involves exposure of neoplastic tissue to radiation designed to kill the cancerous tissue. The technology has advanced to the point where multiple doses can be simultaneously focused on the lesion. This provides higher dosing in the lesion while surrounding tissue is exposed to lower doses of radiation. This technology involves complex algorithms, and dosing errors of an order of magnitude or greater can result. Also, significant collateral damage is inflicted on surrounding tissue.
Brachytherapy uses radioactive “seeds” which must be placed correctly in the tumor or correspondingly inappropriate dosing occurs. The method is very skill-dependent in order to achieve successful outcomes. Brachytherapy has not developed a long record of clinical utility.
Chemotherapy involves the administration of cytotoxic agents to patients. These agents are used because they exhibit selective cytotoxicity, and their action against neoplastic tissue can be up to several times that against normal tissue. Chemotherapy is ordinarily administered systemically, usually in aliquots over periods of several days or weeks. This is done in order to reduce unintended adverse effects that result from systemic drug concentrations which are too high to be tolerated by patients. This method is compromised by the fact that maximum systemic drug doses tolerated by patients produce drug concentrations in tumors that are well below the ideal concentrations required to achieve maximum efficacy. Considerable collateral tissue damage results because of the relatively high systemic drug concentrations that are required to achieve significant anti-tumor activity. Patients may become susceptible to infection because drug infusion and disease can compromise their immune systems.
A major problem with chemotherapy as currently practiced is that much of the drug does not reach the intended target tissue. Systemic drug delivery results in administration of drug to a general compartment (e.g., vasculature) for distribution throughout the body. Some of the drug does reach the intended target site, but most is distributed elsewhere. This “non-targeted” drug is responsible for the adverse effects associated with chemotherapy. Ultimately, of course, the drug is metabolized and excreted from the body.
In contrast, targeted drug delivery provides for the bulk of the drug to be administered directly to the desired site. Some drug still reaches the central compartment for general distribution to non-target tissues, but most of the drug is available for therapeutic effect and only a small fraction results in adverse effects.
Various forms of targeted drug delivery have been investigated in an effort to enhance chemotherapy by increasing drug concentrations in the tumors while reducing the systemic drug concentrations. Targeted chemotherapy has been delivered via catheters into vessels feeding tumors or organs containing tumors. In most cases, the medicament or medicaments wash through the tumor too quickly and thus fail to maintain the sustained high, efficacious in-tumor drug concentrations needed for more effective therapy. The results have been somewhat better than systemic administration of chemotherapy, but not as good as desired. Various other techniques employ systemic administration of one or more medicaments that are intended to selectively absorb onto or into tumors, but these techniques result in undesirably high systemic drug levels.
Whitbourne U.S. Pat. No. 5,997,517 discloses bond coats for binding polymeric compositions (“top coats”) onto various devices. Several examples show top coats comprising polyvinyl pyrrolidone (PVP) and nitrocellulose.
Whitbourne et al U.S. Pat. No. 5,069,899 discloses coatings for medical devices that can contain anti-thrombogenic and anti-microbial compositions. One disclosed coating containing a heparin compound comprised PVP and nitrocellulose (Example 1).
Whitbourne et al U.S. Pat. No. 5,525,348 discloses coating compositions containing anti-thrombogenic and/or anti-microbial agents. The coating contains water-insoluble polymers that may range from hydrophilic to hydrophobic.
Li et al U.S. Pat. No. 5,977,163 discloses a targeted drug delivery technique that involves linking paclitaxel or docetaxel to water soluble chelators, polyethylene glycol or a biodegradable polymer such as polyglutamate (PG-TXL). This linkage makes the paclitaxel or docetaxel water soluble, and causes it to selectively absorb into tumors. For example, animal testing showed that more than 300% of the equivalent maximum human dose of paclitaxel can be achieved. However, this method still involves substantial systemic drug concentrations with all of the potential side affects associated with such dosing levels. The use of water-soluble paclitaxel as a coating on implanted medical devices for the inhibition of restenosis is also discussed (col. 5, line 66-col. 6, line 43; col. 9, lines 23-43).
K. Sato et al (Gan To Kagaku Ryoho 1990, Jun. 17(6):1105-10) discloses selective intraarterial infusion of ethylcellulose microcapsules containing an anticancer drug which exerts its therapeutic affects through infarction and sustained drug action (i.e., chemoembolization). This technique relies on the microcapsules embolizing the tumor vasculature and the subsequent diffusion of one or more drugs throughout the tumor(s). The results were better for bladder cancer (54% substantial tumor reduction (STR)), and prostate carcinoma (54% STR), but results were much lower for renal cell carcinoma and hepatoma.
Kato et al (Cancer Chemother Pharmacol 1996; 37(4):289-96) reviewed the feasibility of intra-arterial infusion of microencapsulated anticancer drugs (chemoembolization). Ethylcellulose microcapsules containing mitomycin C (median total dose 20 mg), cisplatin (60 mg) or peplomycin (40 mg) were given to tumor-feeding arteries by bolus injection. Mitomycin C microcapsules produced a higher response rate. Complete or partial remission of intractable pain and genitourinary gross hemorrhage was found in two-thirds of eligible patients. This modality is promising, but suffers from the inability to target individual tumors, thus patients experience adverse affects, and drug concentrations in the tumors is less than desired relative to the background liver tissue.
Kemeny et al (New England Journal of Medicine 1999; 341:2039-48) treated patients with six cycles of hepatic arterial infusion with floxuridine and dexamethazone plus intravenous fluorouracil, with or without leucovorin. The study showed improvement in survival, but involved systemic infusions of cytotoxic agents and adverse affects were seen in patients.
Caklakli et al (Acta Oncol 1996; 35(4):441-4) evaluated the efficacy of hepatic arterial infusion chemotherapy in the treatment of primary or metastatic liver carcinoma in 37 patients. The infusions were administered through a catheter that was placed in the hepatic artery, either surgically or by percutaneous puncture of the femoral artery. A complete response was observed in four patients. A partial response was observed in six patients and a minor response in another six. In nine patients the disease stabilized, while progression of the disease developed in 12 patients. The response rate (complete, partial, and minor responses) was 43.2% and median survival was 12.0 months. These results are promising. However, there were 17 Grade III toxicities observed, and the therapy was not directed primarily or directly into the patients' tumor or tumors.
The delivery of one or more medicaments to specific sites in a patient's body is an issue in fields other than the treatment of tumors. For example, in clinical practice, new strains of organisms have emerged which exhibit significantly more resistance to antibiotic therapy than do previously known strains. Antibiotics are normally administered systemically, either orally or via intravenous injection, so that systemic concentrations which are safe for most patients are achieved. However, these concentrations are below effective levels in the cases of some of the emerging drug-resistant organism strains. It would be advantageous in many cases if one or more medicaments providing anti-infective therapy could be targeted to infected lesions or other specific sites. In this way, it would be possible to achieve higher, more efficacious drug concentrations in the lesions, while systemic drug concentrations would remain at or below levels which are safe for most patients. As with cancer site-targeted therapy, site-targeted antibiotic therapy would be expected to be significantly more efficacious than systemic treatment.
It will be seen from the foregoing that need exists for achieving efficacious drug or other medicament concentrations in tumors for extended time periods without concurrent high systemic drug concentrations and for targeted delivery of anti-infective agents such as antibiotics, to sites such as infected lesions.